We are studying the biology of ovarian cancer and the mechanisms of antineoplastic drug resistance in human tumors. This has required the development of human ovarian cancer cell lines in tissue culture and in nude mice xenografts. The dose response curves to antineoplastic drugs are generated using a clonogenic assay. Cell lines from previously untreated patients which are sensitive in vitro have been incubated with progressively increasing concentrations of melphalan, adriamycin and cisplatin to produce drug resistant variants. With these sets of cell lines [endogenously resistant, endogenously sensitive, and their resistant variants] we are examining the mechanisms of drug resistance at a cellular level and biochemical manipulations which can restore sensitivity in the resistant cell lines. We have characterized 3 new ovarian cancer cell lines including a line which has steroid hormone receptors. We have also developed drug resistant variants which are 6-10 times more resistant than the primary cultures. We have also developed a new transplantable intraperitoneal model of human ovarian cancer in nude mice which produces ascites, pulmonary metastases and death from intraabdominal carcinomatosis. We have demonstrated that melphalan resistance is linked to glutathione levels. Furthermore, using techniques to alter the levels of glutathione or to change the permeability of cell membranes, we have been able to restore drug sensitivity in melphalan and adriamycin resistant cell lines, respectively. These experimental studies have led to a clinical trial of verapamil plus adriamycin in refractory ovarian cancer patients.